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Tumor-associated neutrophils stimulate T cell responses in early-stage human lung cancer
Evgeniy B. Eruslanov, … , Steven M. Albelda, Sunil Singhal
Evgeniy B. Eruslanov, … , Steven M. Albelda, Sunil Singhal
Published November 10, 2014
Citation Information: J Clin Invest. 2014;124(12):5466-5480. https://doi.org/10.1172/JCI77053.
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Research Article Oncology Article has an altmetric score of 34

Tumor-associated neutrophils stimulate T cell responses in early-stage human lung cancer

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Abstract

Infiltrating inflammatory cells are highly prevalent within the tumor microenvironment and mediate many processes associated with tumor progression; however, the contribution of specific populations remains unclear. For example, the nature and function of tumor-associated neutrophils (TANs) in the cancer microenvironment is largely unknown. The goal of this study was to provide a phenotypic and functional characterization of TANs in surgically resected lung cancer patients. We found that TANs constituted 5%–25% of cells isolated from the digested human lung tumors. Compared with blood neutrophils, TANs displayed an activated phenotype (CD62LloCD54hi) with a distinct repertoire of chemokine receptors that included CCR5, CCR7, CXCR3, and CXCR4. TANs produced substantial quantities of the proinflammatory factors MCP-1, IL-8, MIP-1α, and IL-6, as well as the antiinflammatory IL-1R antagonist. Functionally, both TANs and neutrophils isolated from distant nonmalignant lung tissue were able to stimulate T cell proliferation and IFN-γ release. Cross-talk between TANs and activated T cells led to substantial upregulation of CD54, CD86, OX40L, and 4-1BBL costimulatory molecules on the neutrophil surface, which bolstered T cell proliferation in a positive-feedback loop. Together our results demonstrate that in the earliest stages of lung cancer, TANs are not immunosuppressive, but rather stimulate T cell responses.

Authors

Evgeniy B. Eruslanov, Pratik S. Bhojnagarwala, Jon G. Quatromoni, Tom Li Stephen, Anjana Ranganathan, Charuhas Deshpande, Tatiana Akimova, Anil Vachani, Leslie Litzky, Wayne W. Hancock, José R. Conejo-Garcia, Michael Feldman, Steven M. Albelda, Sunil Singhal

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Figure 4

Characterization of neutrophils isolated from tumor tissues and peripheral blood of patients with NSCLC.

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Characterization of neutrophils isolated from tumor tissues and peripher...
(A and B) Neutrophil survival in vitro. TANs and PBNs were isolated from lung cancer patients with magnetic beads by positive selection. Cells were cultured in cell culture medium with or without TCM for 20 and 48 hours. TANs and PBNs were then assessed for apoptosis by FACS analysis of annexin V/PI staining at 1, 20, and 48 hours. Dot plots represent 1 of 6 similar experiments. Numbers represent the percentage of cells in each quadrant. Summary results from 6 lung cancer patients are also shown (*P ≤ 0.01, Wilcoxon matched-pairs rank test). (C) Production of H2O2 in TANs and PBNs isolated from lung cancer patients and healthy donors was measured using Amplex Red with horseradish peroxidase. Error bars represent mean ± SEM from 5 independent experiments (*P ≤ 0.001, Wilcoxon matched-pairs rank test). (D) Phagocytic capacity of TANs. TANs and PBNs were isolated and incubated with pHrodo Red E. coli BioParticles for 45 minutes to allow phagocytosis (internalized particles become fluorescent [red]). Histograms from 1 representative experiment are shown. Phagocytosis performed at 4°C and 37°C is shown by thin and thick lines, respectively; MFI values are as indicated in histograms. Summary results from 6 lung cancer patients are also shown (Wilcoxon matched-pairs rank test).

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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